Inappropriate activation or inactivation of apoptosis (programmed cell death) can have devastating consequences, from neurodegenerative disease to cancer. This Phase I proposal tests the hypothesis that we can significantly increase the likelihood of finding compounds that regulate cell death by biologically-focused collections, providing, to drug discovery screens, natural products obtained from organisms and/or tissues at times at which cell death is being turned on or off by endogenous regulators. The proposed work also will assess whether our high throughput analytical methods expedite identification of cell death regulators by rapidly focusing attention on specific compounds that appear and disappear during initiation and termination of regulated cell death. Conceptually, our work distinguishes between treatments that may trigger cell death through damage, and molecules that have evolved as endogenous regulators of cell death pathways. "Cell death plates" will be commercialized for screening through collaborations with biotech and pharmaceutical companies. Active compounds will be partnered for clinical development and international marketing. Natural products, although widely used as drugs, often present bioavailabilty and/or manufacturing challenges. By increasing the rate of discovery of active natural products through focused collection, we seek to increase the probability of discovery of molecules that will prove to be of practical medical importance. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE